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Early menopause a risk factor for type 2 diabetes

Publish date: October 14,
2016

Author(s): Kari Oakes

Early age at menopause was
associated with the incidence of type 2 diabetes,
independent of obesity and a host of other potentially
confounding factors, in a prospective study.

“What we see in our data is
that indeed, early onset of menopause is associated with
increased risk of type 2 diabetes, and this association is
independent of potential intermediate risk factors: obesity,
insulin, glucose, inflammation, but also of estradiol and
other endogenous sex hormone levels,” said Taulant Muka, MD,
PhD, in an interview. Dr. Muka, a postdoctoral fellow at
Erasmus Medical College, Rotterdam, the Netherlands,
presented the analysis from a large, prospective cohort of
menopausal women at the annual meeting of the North American
Menopause Society.

Among the 3,210 participants
in the prospective Rotterdam study, 319 incident cases of
diabetes were identified over the median 10.9-year follow-up
period, with a relative risk for incident diabetes of 2.29
for women undergoing menopause before the age of 40, and
1.49 for those experiencing menopause between age 40 and 44.

In an interview, Dr. Muka
noted that the study investigated whether the association
between early age at natural menopause (ANM) and type 2
diabetes is independent of intermediate risk factors for
type 2 diabetes, such as obesity. Finally, the study also
assessed whether endogenous sex hormone levels play a role
in the link between early ANM and type 2 diabetes.

Enrollment in the Rotterdam
study has been continuing in waves since the 1990s, with
enrollment for participants in this particular study cohort
occurring in 1997 and with additional cohorts enrolled in
2000-2001 and 2006-2008.

“I think this is the first
prospective study with such long follow-up data and with a
broad adjustment for confounding factors. Previous studies
have been mainly cross-sectional, providing conflicting
results,” said Dr. Muka.

Using self-reported age at
menopause, the investigators excluded from the study women
whose menopausal status was not known, who were actually not
menopausal, or whose menopause had not occurred naturally.
The study population also excluded women with prevalent type
2 diabetes or for whom no information about diabetes
follow-up could be found.

The remaining 3,210 women
who were included in the study had a median age of 67 years
and had reached menopause at a median of 49.9 years. Most
women (82.6%) had an ANM of 45-55 years; ANM for 8.8% was
40-44 years, while just 2.3% had an ANM of under 40 years.
Mean body mass index was 27.1 kg/m2.
Participants were considered to have incident diabetes based
on several sources: a general practitioner’s records,
hospital discharge paperwork, or glucose measurements from
visits during the Rotterdam study. Participants also were
classified as having diabetes if they used a hypoglycemic
medication or had a fasting blood glucose level of at least
7 mmol/L (126 mg/dL) or, in the absence of a fasting blood
glucose measurement, a nonfasting blood glucose of at least
11.1 mmol/L (200 mg/dL).

Dr. Muka said he and his
coinvestigators identified and adjusted for a large number
of variables, using a series of three Cox proportion hazard
models.

The first model adjusted for
age, which wave of enrollment (cohort) participants were in,
hormone therapy status, age at menarche, and the number of
pregnancies that reached at least 6 months’ gestation.

The second model used all of
the factors in model 1, and added BMI and glucose and
insulin levels. The third model used all of the factors in
model 2, and also added total cholesterol level, systolic
blood pressure, the use of lipid-lowering or
antihypertensive medications, alcohol and tobacco use,
educational level, prevalent cardiovascular disease, and
C-reactive protein levels.

The association of early ANM
with the risk of type 2 diabetes was statistically
significant in all three models (P less than .001), with
very similar hazard ratios (HRs) in all models. For the
third, the most comprehensive model, the HR was 1.42 (95%
confidence interval, 0.83-2.45).

Extensive sensitivity
analyses were carried out, and the association held
independent of physical activity level, smoking status, use
of hormone therapy, and age. The investigators also used
multivariable analyses to ensure that the effect was not
mediated by serum levels of thyroid-stimulating hormone,
dihydroepiandosterone (DHEA) and DHEA sulfate, estradiol,
testosterone, sex hormone–binding globulin (SHBG), or
androstenedione.

This study was the first in
this population to obtain and adjust for serum sex hormone
and SHBG levels, said Dr. Muka.
The prospective design of the study and the long follow-up
period were study strengths, said Dr. Muka. Additionally,
blood glucose readings taken at study visits, together with
electronically linked pharmacy dispensing records were used
for incident diabetes diagnoses.

Study limitations, Dr. Muka
said, included the possibility of survival bias, since
enrollees “may represent survivors of early menopause who
did not develop [type 2 diabetes] or die prior to
enrollment.” However, he said, this would mean that “we have
underestimated the association, so the risk would be even
higher.” Also, all study participants were white, so the
results cannot be extrapolated to nonwhite populations.

Dr. Muka said that the
largely American audience for his presentation was
interested in the fact that the association existed
independent of BMI, an obesity marker, based on questions
and comments following the talk. “Indeed, we stratified the
analysis, and we didn’t find any difference between
participants who were obese and nonobese.” Also, he said
that there were queries about whether the analyses had
corrected for DEXA measurements, in order to assess lean
versus fat body composition more accurately. This analysis
has not been done, but Dr. Muka plans to complete it on his
return to Rotterdam, he said.

Up to 10% of women will
reach menopause before the age of 45, said Dr. Muka, so this
analysis has the potential to impact primary care for
millions of women. “Women who undergo early menopause may be
a target for type 2 diabetes prevention measures and might
need to be screened for other cardiovascular risk factors
like high blood pressure and dyslipidemia, since they are
also at risk for cardiovascular disease.”